PAS: Nitric Oxide Lowers Lung Risk for Premature Infants

Action Points

Explain to interested patients that inhaled nitric oxide given to premature newborns seems to lessen their chances of developing chronic lung disease.

Note that these studies suggest the benefit occurs without a significant risk of adverse events.

These studies were published as abstracts and presented orally at a conference. The data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.

But the benefit only came when the gas was given not later than seven to 14 days after birth, said Roberta Ballard, M.D., of the Children's Hospital of Philadelphia, in a late-breaking presentation at the Pediatric Academic Societies meeting here.

The finding emerged from a multicenter, national study, in which nearly 600 babies were randomized to nitric oxide or placebo gas, Dr. Ballard reported on behalf of the NO-CLD Study Group.

In animal models, inhaled nitric oxide improves gas exchange and lung structural development, but the use of the gas in infants has been a subject of debate, Dr. Ballard reported, which led to the randomized stratified, double-blind, placebo-controlled trial at 21 U.S. centers.

Eligible were infants whose birth weight was less than 1,250 grams and who needed ventilator support at seven to 21 days of age. Treated infants got decreasing amount of nitric oxide, starting at 20 parts per million, for at least 24 days.

The 294 infants who got the treatment gas were comparable to the 288 who got placebo in all baseline characteristics, Dr. Ballard reported. Specifically, the treated group had an average birth weight of 766 grams versus 759 grams for the placebo group. Gestational age was identical at 26 weeks, and age at entry was 16 days on average in both groups.

The study found:

The rate of survival without chronic lung disease at 36 weeks postmenstrual age was higher in treated infants than in the placebo groupâ€”43.9% versus 36.8%, respectively. The difference was statistically significant at P=0.042.

The trend toward benefit was similar for infants of 500 to 799 grams and 800 to 1,250 grams.

Severity of lung disease, based on hospitalization and requirement for ventilator support, was less for the treated group at 36, 40 and 44 weeks. The differences were significant at P=0.012, p=0.014, and P=0.033, respectively.

The groups did not differ with respect to co-morbidities occurring after entry.

In a post-hoc analysis, Dr. Ballard reported, the investigators found that inhaled nitric oxide improved survival without chronic lung disease only for infants enrolled between seven and 14 days after birthâ€”49.1% of the treated group versus 27.8% of the placebo group. The result was significant at P=0.001.

However there was little difference between infants enrolled between 15 and 21 days after birth. The rates were 40.7% and 42.8% for the treated and placebo groups respectively.

The benefit was seen mainly in infants with less severe lung disease at entry, Dr. Ballard reported.

In a second late-breaking presentation at the meeting, a group led by Steven Adman, M.D., of the University of Colorado Health Sciences Center in Denver reported a similar result, using nitric oxide to reduce bronchopulmonary dysplasia and death without increasing brain injury in some premature infants who needed mechanical ventilation in the first 48 hours of life.

The study randomized 793 premature newborns of gestational age less than 34 weeks with respiratory failure to get either five parts per million of the treatment gas (n=398) or placebo (n=395) for 21 days or until extubation.

Overall, the researchers reported, there was no difference in the incidence of death or bronchopulmonary dysplasia between groups.

But for infants with a birth weight greater than 1,000 grams, the therapy reduced the incidence of bronchopulmonary dysplasia by 50%, a difference that was statistically significant at P=0.00l.

Also, for the entire study population the therapy reduced the incidence of periventricular leukomalacia (significant at P=0.048), as well as the combined endpoint of intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly (significant at P=0.032).

There was no increase in adverse events in any birth weight subgroup.

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine

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